PROCESS FOR THE PREPARATION OF N-4-[(SUBSTITUTED PHENYL)ALKYLTHIENYL]-, AND N-4-[(SUBSTITUTED PHENYL)ALKYLFURYL]BUT-3-YN-2-YL]-N-HYDROXYUREA COMPOUNDS

Abstract: A process for preparing a compound of structure (I), where A is oxygen and sulfur and R<1> is selected from the group consisting of hydrogen, halogen, alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, and trifluoromethyl, and R<2> is alkyl of one to four carbon atoms, comprising coupling a compound of formula (II), where X is bromine or iodine, with an N-hydroxyurea compound of formula (III), in the presence of a palladium catalyst. The compounds of formula (I) are inhibitors of the enzyme 5-lipoxygenase and are thus useful as therapeutic agents for the treatment of allergic and inflammatory disease conditions.

Description: Process for the Preparation of of N-4- [(Substituted Phenyl)alkylthienyl]-, and N-4-[(Substituted Phenyl)alkyIfuryl]but-3-yn-2-yl]- N-Hydroxyurea Compounds Technical Field The present invention relates to chemical synthetic processes. More particularly, the present invention concerns a process for the preparation of a class of N-4-[(substituted phenyl)alkylthienyl]-, and N-4- [(substituted phenyl)alkyl- furyl]but-3-yn-2-yl]-N-hydroxyurea compounds. Background of the Invention Compounds of structure I where A is oxygen or sulfur and Rl is alkyl, halogen, alkoxy, or trifluoromethyl, have been found to be effective inhibitors of the enzyme 5-lipoxygenase. This enzyme is involved in the conversion in the human body of arachidonic acid to the leukotrienes which have been implicated in inflammatory disease conditions. The compounds are thus useful therapeutic agents in the treatment of asthma, arthiritis, inflammatory bowel syndrome, and similar conditions. Summary of the Invention In its broadest aspect, the present invention provides an efficient and cost- effective process for the preparation of a compound having the structure: I where A is oxygen or sulfur and Rl is selected from hydrogen, halogen, alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, and trifluoromethyl and R-2 is hydrogen or alkyl of one to four carbon atoms. The process comprises the step of coupling a compound of formula II: « XjQrr χ II where R and A are as defined above and X is bromine or iodine, with a compound of formula III: OH R 3 R 2 III where R*^ is as defined above and R**-- is selected from hydrogen or -C(O)NH2, and thereafter, in the instance where R3 is hydrogen, reacting the product of the first coupling step with an alkali metal isocyanate. The present invention also encompasses process for making the intermediates II and III for the coupling reaction decribed above. Detailed Description As used throughout this specification and the appended claims, various terms and phrases have the meanings ascribed to them as follows. By "alkyl" is meant a monovalent group which can be thought of as deriving from a straight or branched saturated hydrocarbon by the removal of a single hydrogen atom. "Alkoxy" denotes an alkyl group as defined above, attached to the parent molecular moiety through an oxygen atom. In general, the process of the present invention involves three distinct phases, including 1) the synthesis of the so-called "lefthand" (substituted phenylalkyl)thienyl- or -furyl,halide portion; II, 2) the synthesis of the so-called "righthand" N-hydroxyurea portion. Ill, and 3) coupling of the two precursor halves, II and III, to form the final product, I. These parts of the total synthesis are termed "phases" of the process rather than steps, since it is to be understood that the preparation of the righthand and lefthand portions of the molecule can be carried out in any order and are thus not "steps" of the process in the usual sense of the term. The final step of joining or coupling the two precursors molecules must, of course, follow their prior synthesis. Preferred Method of Synthesizing the "Lefthand" Precursor. II The lefthand (substituted phenyl)alkylfuran or (substituted phenyl)alkylthienyl precursor is preferably synthesized by the reaction sequence depicted in Reaction Scheme 1. Reaction Scheme 1 la, A = O 2a, A = O lb, A = S 2b, A = S 4a, X = Br 4b, X = I X = Br or I 5a, A = O 5b, A = S 'Ouu HIO 3 , 1 2 R 'OUU H + 5a, A = O 6a, X = O 5b, A = S 6b, X = S The appropriate commercially available R ^substituted benzyl chloride, 3, is converted to the corresponding R ----substituted benzyl bromide, 4a, or benzyl iodide, 4b, (preferably the benzyl iodide), by reaction with either lithium bromide or sodium iodide in a suitable polar aprotic organic solvent such as tetrahydrofuran. Commercially available 2-bromofuran, la, or 2-bromothiophene, lb, is converted under typical Grignard reaction conditions to the corresponding Grignard reagent, 2a or 2b. The R 1 -substituted benzyl bromide, 4a, or iodide, 4b, is then reacted with the thienyl or furyl Grignard reagent in tetrahydrofuran in the presence of lithium tetrachlorocopper (II) which acts as a coupling catalyst to yield the desired R 1 - substituted benzylfuran, 5a, or benzylthiophene, 5b. The R -substituted benzylfuran, 5a, or benzylthiophene, 5b, is finally converted to the 5-(R*- substituted phenyl)-2-iodo- or bromofuran, 6a, or thiophene, 6b, by reaction with iodine in the presence of HIO3 or reaction with bromine. The iodination reaction is carried out typically at temperatures ranging between ambient and about 50°C, preferably at about 30°C to about 40°C for periods ranging between about 5 to about 24 hours. A typical reaction time is overnight. The bromination is carried out under conditions typical for bromination of aromatic systems. Alternative Methods of Synthesizing the "Lefthand" Precursor Although the synthetic method depicted in Reaction Sequence 1 above is the preferred method of forming compounds of the structure 5a or 5b, various other methods can be employed for the synthesis of intermediate II. While these alternatives methods are acceptable, they are generally less desirable because of one or more shortcomings such as diminished yield, utilization of costly starting materials, or production of mixtures requiring separation. The following are examples of alternative methods of preparing compounds of the structure of II. Alternative 1 - Friedel-Crafts alkylation (Illustrated with thiophene and 4- fluorobenzyl chloride, bromide, or iodide) 7a, X = Cl 7b, X = Br 7c, X = I Friedel-Crafts alkylation of thiophene with 4-fluorobenzyl chloride, 4-fluorobenzyl bromide or 4-fluorobenzyl iodide) in the presence of a Lewis acid catalyst (AICI3, ZnCl2, or EPZ10) were found to produce a mixture of 2- and 3-alkylation products in roughly equal amounts. The resulting reduced yield of the desired product and the separation of the product mixture makes this process less desirable. Alternative 2 - Transition metal catalyzed coupling of Grignard reagents (illustrated with 2-bromothiophene and 4-fluorobenzyl bromide) The Nickel catalyzed coupling reaction of 4-fluorobenzylzinc bromide and the Grignard reagent derived from 2-bromothiophene failed to produce 2-(4- fluorobenzyl)thiophene in reasonable yield. Although several different methods for activating the zinc were used to prepare the organozinc reagent, all of them failed to improve the yield. Alternative 3 - Transition metal catalyzed coupling of a substituted benzyl halide with a Grignard reagent (Illustrated with 4-fluorobenzyl chloride, bromide or iodide and the Grignard reagent derived from 2-bromothiophene) 7a, X = Cl 7b, X = Br 7c, X = I The Nickel catalyzed coupling reaction of the Grignard reagent derived from 2-bromothiophene with 4-fluorobenzyl chloride, 4-fluorobenzyl bromide or 4-fluorobenzyl iodide was found to work well in small scale (10 mmol), but when attempts were made to scale the reaction up (100 mmol), numerous undesired by¬ products were produced. Alternative 4 - "Kumada" coupling of the Grignard reagent derived from a substituted benzyl halide with 2-bromothiophene (Illustrated with the Grignard reagent derived from 4-fluorobenzyl chloride and 2-bromothiophene) 7a 11 lb 8 Kumada, Tetrahedron. 38: 3347 (1982) has described the production of 2- benzyl thiophene by the coupling reaction illustrated above for the 4-fluorobenzyl starting material. The process has the disadvantage that the reaction is carried out in diethyl ether, which is highly flammable. Alternative 5 - A two step Grignard process: 8 This process involves an addition of an aldehyde to a thiophene Grignard followed by deoxygenation of the resulting secondary alcohol. The quality of the product is not good enough for use in the next step without purification by vacuum distillation. Alternative 6 - Alkylation of furyl- or thienyllithium (Illustrated with 4-fluorobenzyl bromide and 2-lithiothiophene) nn--BBuuttyyll lliitthhiiuumm O * S^ T THHFF iXJ 14 8 This process, while effective in producing the desired intermediate, 8, suffers from the disadvantage that it requires the use of n-butyl lithium. The hazards associated with its use on a large scale preclude this method from choice for commercial-scale production of the intermediate, 8. Preferred Method of Synthesizing the "Righthand" Alkynic N-Hydroxyurea Precursor. Ill The righthand precursor portion of the end-product of the process of this invention is an N-acetylenic-N-hydroxyurea compound of structure III: III The substituent group R 2 may be hydrogen or alkyl of one to four carbon atoms. The preferred compound of the process of this invention is that in which R 2 is methyl. When R 2 is other than hydrogen, there is a chiral center in compounds of structure in at the carbon atom which bears the R 2 substituent. The present invention contemplates process for making both enantiomers of III, as well as mixtures of the two including the racemic mixture. In addition, the present invention contemplates processes for making both enantiomers of the final products of structure I above. The latter process is a natural consequence of the former; that is, once the desired enantiomer or enantiomeric mixture of III is produced, coupling of that material with an intermediate of structure II above results in the desired enantiomeric form of I or enantiomeric mixture, since the coupling reaction does not affect the chiral center. The preferred method of synthesizing the righthand precursor is depicted in Reaction Scheme 2 where, for the sake of illustration, the reaction sequence employs the preferred S-3-butynol (i.e. R 2 = methyl). It is to be understood, however, that the same reaction sequence can be employed with other starting alcohols corresponding to R 2 being alkyl of two to four carbon atoms, or with the non-chiral alcohol, propynol (R 2 = hydrogen). Reaction Scheme 2 Referring to Reaction Sequence 2, the preferred S-enantiomer of 3-butynol, 15, is converted to the corresponding methanesulfonic acid ester ("mesylate"), 16, by conventional means. The reaction is typically carried by reacting methanesulfonyl chloride with the alcohol at lower temperatures, generally about 0°C to about room temperature, preferably about 0°C to about 10°C, in an inert organic solvent such as methylene chloride. An acid scavenger such as a tertiary amine (e.g. triethylamine) is employed in the reaction mixture. Reaction times range from about one-half to six hours, typically from about one to two hours for substantially complete conversion of the alcohol to the methanesulfonate ("mesylate") 16. Although the mesylate is preferred, other butynol derivatives e.g. the p- toluenesulfonate ("tosylate"), and the triflate may also be employed in this step of the process. The tosylate and triflate of 3-butynol were also prepared and their reaction with aqueous hydroxylamine proceeded smoothly following the treatment with KOCN HC1 to give 18 in comparable yields. In the next step, the mesylate, 16, is reacted with 50% hydroxylamine, resulting in a typical Sn2 nucleophilic displacement of the methansulfonate leaving group to produce the inverted hydroxylamine, 17. The displacement reaction can be carried out in methanol, ethanol, isopropanol or THF as the reaction solvent resulting in overall production of compound 18 in yields uniformly exceeding 85%. This reaction appears to produce almost complete inversion at the chiral center. Thus, if the desired hydroxylamine is the preferred R-enantiomer, the starting alcohol of choice is the S-3-butynol. For the production of the S- hydroxylamine, the desired starting material is the R-3-butynol and, of course, racemic alcohol produces the racemic hydroxylamine. Racemic 3-butynol and the R- and S-enantiomeric forms are commercially available or may be made by various methods including resolution by conversion to an ester followed by enzymatic hydrolysis to produce a mixture of one enantiomer of the alcohol and the ester of the other followed by conventional physical 1 separation. Alternatively, the racemic alcohol may be preferentially esterified by enzyme catalysis to produce a mixture of one enantiomer of the alcohol and an ester of the other, followed by physical separation. In the final step, the hydroxylamine, 17, is reacted with an alkali metal isocyanate such as potassium isocyanate to produce the desired single enantiomer N-hydroxyurea intermediate, 18. In the process described above the starting alcohol, S-3-butynol, is preferably converted to a derivative in which the alcohol oxygen atom is derivatized by a methanesulfomate leaving group. Other leaving groups which may be used include the p-toluenesulfonate ("tosylate"), p-chlorophenylsulfonate, and trifluoromethylsulfonate ("triflate"). The leaving group on the 3-butynol is displaced by a nucleophile which effects the replacement of the alcohol oxygen atom with a nitrogen, from which an N-hydroxylamine or urea ultimately derives. Suitable nucleophiles include hydroxylamine, hydroxylamine hydrochloride, and reagents of the structure ^ R R 4 19 in which R3 and R^ are independently lower alkoxy, phenoxy or substituted phenoxy. The synthesis of reagents of this type is described by Stewart and Brooks in J. Or . Chem.. 57(18): 5020-5023 (1992). Displacement of the leaving group on the S-3-butynol by the nucleophile is generally carried out in the presence of a base such as an alkali metal carbonate or bicarbonate such as potassium or sodium carbonate or bicarbonate, alkali metal alkoxides such as potassium t-butoxide, alkali metal hydrides such as sodium hydride, n-butyl lithium, pyridine, 2,6-lutidine, and the like. Suitable solvents include tetrahydrofuran, dimethylformamide, dimethylsulfoxide, methylene chloride, pyridine, acetonitrile and the like. Alternative Method of Making the "Righthand" N-Hvdroxyurea Precursor. Ill R = methoxy In one alternative method, mesylate, 16, is reacted with a reagent, 19a, or 19b, in a suitable aprotic organic solvent such as tetrahydrofuran, followed by reaction of the product thus formed with aqueous ammonia to produce the desired enantiomeric N-hydroxyurea, 18. The process results in 18 in good yield, generally exceeding 80%. Preferred Method of Coupling II and III to form I: In the last stage of the method of this invention, the so-called "lefthand" piece, II, is coupled to the righthand piece, III. The coupling process is carried out in any one of a number of suitable solvents selected from dimethylformamide, acetonitrile, ethyl acetate, dichloromethane, or a biphasic system comprising isopropyl acetate and water. The coupling reaction is generally carried out in the presence of a base such as triethylamine, diethylamine, diisopropylamine, isopropylamine, potassium or sodium carbonate, or sodium acetate. Either the substituted 2-bromo- or 2-iodothiophene, can be coupled with the righthand N-hydroxyurea piece, III, although the substituted 2-bromothiophene produced somewhat lower yield and required longer reaction times. The coupling is catalyzed by a palladium catalyst which may take the form of PdCl2, PdOAc2, (CH3CN)2PdCl2 , Pd(PPh3)4, and polymer supported Pd(0) with (CH3CN)2PdCl2 being the preferred catalyst. Example 1 Preparation of 4-Fluorobenzyl bromide and iodide Step 1 - Preparation of Li2CuCl4 solution The solution was prepared by mixing lithium chloride (0.85 g, 20 mmol) and copper chloride (1.35 g, 10 mmol) in THF ( 100 ml) at room temperature for 1 hour. Step 2 - Preparation of 4-fluorobenzyl bromide A mixture of 4-fluorobenzyl chloride (14.46 g, 0.1 mol) and LiBr (17.4 g, 0.2 mol) in THF (15 ml) was heated to 65°C ~ 70°C for 2 hours (GC-MS showed that all the 4- fluorobenzyl chloride was converted to the 4- fluorobenzyl bromide). The mixture was cooled to room temperature, filtered and the flask was rinsed with THF (20 ml). The combined filtrate was used in the next step directly. Step 3 -Preparation of 4-fluorobenzyl iodide A mixture of 4-fluorobenzyl chloride (14.46 g, 0.1 mol) and Nal (18.0 g, 0.12 mol) in THF (50 ml) was heated to 65°C ~ 70°C for 3 h (GC-MS showed that all the 4- fluorobenzyl chloride was converted to the 4-fluorobenzyl iodide). The mixture was cooled to room temperature and was used in the next step directly. Example 2 Preparation of of 2-C4-fluorobenzyl')thiophene To a suspension of Mg turnings (3 g, 0.123 mol) in THF (40 ml) was added a small amount of solid 12 (20 mg). The mixture was heated to reflux under nitrogen. To the mixture was then added the 2-bromothiophene solution (5 ml) (19.6 g of 2-bromothiophene in 40 ml of THF). After the iodine color disappeared, to the suspension was added the rest of 2-bromothiophene solution dropwise keeping reflux. After the addition, the mixture was heated under reflux for 2 h., then was cooled to room temperature. To this mixture was added 4-fluorobenzyl iodide (or 4-fluorobenzyl bromide) followed by Li2CuCl4 (5 ml) solution keeping the temperature under 40°C using a cool water bath. The mixture was stirred at room temperature for 2 h. To the mixture was added sat. NH4CI solution (100 ml), the mixture was stirred for 30 min., the organic layer was separated and washed with 10% sodium thiosulfate solution (50 ml), followed by distilled water (100 ml). The organic layer was then dried over MgSO4 and concentrated to give 19 g of 2-(4- fluorobenzyl)thiophene as an oil. Purification can be achieved by vacuum distillation (110°C, 5mmHg). Example 3 Preparation of 5-(4-FluorobenzylV2-iodo ' thiophene A mixture of 2-(4-fluorobenzyl)thiophene (8.4 g, 43.7 mmol), HIO3 (1.86 g, 10.6 mmol), I2 (4.86 g, 19.2 mmol), iso-propyl acetate (66 ml), acetic acid (7.7 ml) and cone. 5 H2SO4 (0.79 ml) was heated at 35°C overnight (GC-MS showed that all the starting material is converted to 5-(4-fluorobenzyl)-2-iodothiophene). To the reaction mixture was added brine solution (33 ml), the organic layer was separated and washed with sodium hydroxide / sodium thiosulfate solution (33 ml) (prepared from 2.3 g of NaOH, 3.3 g of Na2S2θ3 in 27 ml of H2O), followed by 10% of NaHCO3 solution (33 ml). The organic ° layer was filtered and dried to yield 13.9 g of 5-(4-fluorophenyl)-2-iodothiophene. Example 4 Synthesis of R-(+ -N-C3-butvn-2-vπ-N-hvdroxyurea A IL three-neck flask equipped with mechanical stirrer, reflux condensor 5 and a dropping funnel was charged with S-3-butynol, 15, (35. Og, 0.5 mol) in CH- 2CI2 (500 mL). The mixture was cooled to 5°C and triethylamine (65.5g, 90 mL, 0.65 mol) was added. Methanesulfonyl chloride (78.5g, 46 mL, 0.6 mol) was added dropwise keeping the temperature below 10°C. The reaction mixture was stirred at 5°C-10°C for 1.5 h and 0.5N HC1 (300 mL) was cautiously added. The organic 0 layer was separated and washed with saturated NaCl solution (2 x 150 mL). It was then dried (MgSO4) and concentrated under vacuo to give 74.0g (~ 100%) of the mesylate as a light yellow liquid. The mesylate was dissolved in methanol (500 mL) and 50% aqueous NH2OH (300 mL, 5 mol) was added. The mixture was stirred at 23 ° C for 16 hours and then concentrated under vacuo (below 40°C) to 350 5 mL and pH of the mixture adjusted to pH 9 using 40% NaOH solution. The mixture was then extracted with ethyl acetate (5 X 300 mL). The combined ethyl acetate extract was cooled to 5°C and a freshly prepared solution of KOCN (81.0g, 1 mol) in water (150 mL) was added. Keeping the temperature below 10°C, cone. HC1 (100 mL) was added dropwise. The mixture was stirred for 30 min, the organic 0 layer was separated and the aqueous layer was extracted with (5 X 400 mL) ethyl acetate. The extracts were combined with the organic layer, dried (MgSO4), concentrated under vacuo to -150 mL, and heptane (600 mL) was added with vigorous stirring. The solid was filtered, washed with heptane and dried to give 55.0g (86%) of R-(+)-N-(3-butyn-2-yl)-N-hydroxyurea as a light yellow solid. Example 5 Preparation of N-(4-(5-(4-Fluorobenzv thien-2-yl)but-3-vn-2-yl)-N-hvdroxyurea A 500 mL three-neck flask equipped with mechanical stirrer and nitrogen inlet was charged with 6b (R 1 = 4-fluoro), (31.8g, 0.1 mol), 18 (12.8g, 0.1 mol), 5 (CH3CN)2PdCl2 (129mg, 0.5 mmol), PPh3 (262 mg, 1.0 mmol), Cul (190mg, 1.0 mmol) and isopropyl acetate (200 mL). To this mixture, di-isopropylamine (ll.lg, 15.4 mL, 0.11 mol) was added and it was stirred at 23 °C for 2.5 h. A solution of ammonium hydroxide (20%, 150 mL) was added and the mixture was stirred for 30 min. Heptane (400 mL) was added and the mixture was stirred for 15 min. The o solid product was filtered, washed with water (2 X 100 mL), heptane (2 XlOO mL) and dried to give N-(4-(5-(4-fluorobenzyl)thien-2-yl)but-3-yn-2-yl)-N-hydfoxyurea (28.2g, 88.7%) as a light yellow solid. The crude product was recrystallized from EtOAc/heptane 5 While there have been described what are believed to be the preferred embodiments of the process of the present invention, it will be apparent to one of ordinary skill in the art that various modifications may be made in the described process without departing from the scope of the invention as defined by the appended claims.

Claims: WE CLAIM: 1. A process for preparing a compound of the structure I I where 5 A is selected from oxygen and sulfur; R-** is selected from the group consisting of hydrogen, halogen, o alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, and trifluoromethyl; and R2 is hydrogen or alkyl of one to four carbon atoms; 5 comprising coupling a compound of formula II: 0 where R * ' and A are as defined above and X is bromine or iodine, with an N-hydroxyurea compound of formula III: OH ■ N. 3 R J R 2 5 III O where R2 is as defined above and R** is hydrogen or 2 followed by reaction with an alkali metal isocyanate when R3 is hydrogen. 2. The process of Claim 1 wherein said coupling reaction is carried out in the presence of a palladium catalyst. 3. The process of Claim 2 wherein said palladium catalyst is selected from the group consisting of PdCl2, Pd(OAc)2, (CH3CN)2PdCl2, and Pd(PPh3)4. 4. The process of Claim 1 further comprising the steps of preparing the intermediate, II: O rj r, Y , II 5 by a process comprising the steps of a) reacting a Grignard reagent of the formula: with an intermediate of the fomula: o where X is bromine or iodine, in the presence of a copper or nickel catalyst; and b) conversion of the product of step a) to compound II above where Y is bromine or iodine. 5. The process of Claim 4 wherein said copper catalyst is Li2CuCLj.. 6. The process of Claim 4 wherein step b) comprises reacting the product of step a) with iodine in the presence of HIO3. 7. The process of Claim 1 further comprising the steps of preparing the intermediate, III: πi comprising the steps of a) reacting a derivative of an alcohol of the formula r .. L R 2 where L is a leaving group selected from methanesulfonyl, trifluoromethylsulfonyl, p-toluenesulfonyl, and p-chlorophenylsulfonyl, with a nucleophilic reagent selected from hydroxylamine, hydroxylamine hydrochloride, and O ^ R 3 R 4 where R^ and R^ are independently selected from alkoxy of one to four carbon atoms, and phenoxy; b) reacting the product of step a) when said nucleohile is O R 4 with NH3 or NH4OH; or reacting the product of step a) when said nucleophile is hydroxylamine or hydroxylamine hydrochloride with an alkali metal isocyanate. 8. The process of Claim 6 wherein said alcohol derivative is the methanesulfonate. 9. A process for preparing a compound of the structure comprising coupling an intermediate of the structure where Y is bromine or iodine; with an intermediate of the structure: in the presence of a palladium catalyst selected from PdCl2, Pd(OAc)2, (CH3CN)2PdCl2, and Pd(PPh3)4. 10. The process of Claim 9 wherein said palladium catalyst is (CH3CN)2PdCl2.

Inventors: BUSSE JULIETTE K, CHEMBURKAR SAN JAY R, DICKMAN DANIEL A, KU YI-YIN, PATEL HEMANTKUMAR H, PATEL RAMESH R, RATAJCZYK JAMES D, SAWICK DAVID P, BUSSE, JULIETTE, K., CHEMBURKAR, SAN JAY, R., DICKMAN, DANIEL, A., KU, YI-YIN, PATEL, HEMANTKUMAR, H., PATEL, RAMESH, R., RATAJCZYK, JAMES, D., SAWICK, DAVID, P.
Applicants: ABBOTT LAB, ABBOTT LABORATORIES
Application year: 1994
Main classification: C07D333
IPC codes: A61K31, A61P29, A61P37, A61P43, B01J27, B01J31, C07D307, C07D333